Publications

CONCLUSIONS: Over a decade, the proportion of children with CCCs needing PICU care has grown, with trends toward increasing prevalence in the clinically dominant categories of respiratory and hematology, immunodeficiency, and immunology, and the subcategories respiratory malformations, hereditary hemostasis anomalies, and home ventilation, and trends toward higher mortality rates following treatment withdrawal.

In this study, we employ Bayesian optimization to identify conditions for enzyme-catalyzed, site-selective esterifications of pyranoside derivatives. Our findings indicate that Bayesian algorithms facilitate these challenging optimizations, which involve simultaneous variation of enzyme identity, solvent, acyl donor loading, time and temperature, across a range of substrates with various configurations, protective groups and anomeric substituents. Using the experimental optimization data...

A common approach for detecting rare variants (RVs) associated with complex human diseases is to perform a gene-based analysis or a region-based test of association. Typically, in a gene-based analysis, all the RVs pertaining to the gene considered are included in the statistical test, which potentially reduces its power since most RVs are likely not associated with the outcome of interest. As paradigm shift, we propose to add a variable selection step to choose the RVs that compose the...

The phytopathogen Pseudomonas syringae must enter the leaf interior through natural openings such as stomata to cause disease. Plants restrict pathogen entry into the leaf through non-self-recognition-driven stomatal closure. P. syringae counters this stomatal immunity by deploying a range of toxins and effectors. Here, we show that stomatal immunity in Arabidopsis thaliana is reinforced upon recognition of the ubiquitous P. syringae type III effector AvrE1 by the resistance protein CAR1. CAR1...

CONCLUSIONS: Structural brain aging in MDD is age-dependent and most pronounced in a neuroanatomical phenotype associated with poorer key clinical outcomes. The findings are consistent with, but do not establish, neuroprogression models of MDD and demonstrate that cBAG is not a uniform feature of MDD, being more strongly expressed in a specifically clinically vulnerable disease phenotype.

CONCLUSIONS: Career sustainability requires reducing avoidable occupational load while preserving physical capacity and restoring function through recognition, modification, conditioning, recovery, assessment, and rehabilitation.

CONCLUSIONS: The C2PS is a pragmatic and reliable tool to harmonize heterogeneous neuropsychiatric phenotypic data for large multi-national studies. Observations in 1,325 individuals with CNVs at 16p11.2 or 22q11.2 reveal variant-specific psychiatric profiles, emphasize burden and impact of psychiatric multimorbidity, and provide insights beyond categorical diagnoses.

CONCLUSIONS: Proton re-RT demonstrated encouraging locoregional control and survival in heavily pretreated patients, although late toxicities remain important concerns (ClinicalTrials.gov identifier: NCT03217188).

Biophysical pleiotropy, the phenomenon in which a mutation affects multiple protein properties, underlies many genetic diseases and shapes protein evolution, yet remains poorly understood, limiting synthetic biology and therapeutic development. Although extensively studied in soluble proteins, little is known about how pleiotropic effects shaped the evolution of receptor protein functions. Here, we developed a cell-based assay designed to assess pleiotropic effects in G protein-coupled receptors...

CONCLUSIONS AND RELEVANCE: In this systematic analysis, the burden of bone cancer varied by age, geography, and time, underscoring global disparities. These findings provide valuable insights to inform health system planning and resource allocation tailored to different settings.

Proteins shuttle between the nucleus and cytoplasm through the nuclear pore and via nuclear transport receptors, termed importins and exportins. Although genetic alterations involving nucleoporins are enriched in pediatric, adolescent, and young adult (AYA) acute myeloid leukemia (AML), nucleocytoplasmic transport has not been extensively studied in this disease. We discover that genes encoding nucleocytoplasmic transport pathway components (Kyoto Encyclopedia of Genes and Genomes [KEGG]:...

Restricting the centromere-specific histone H3 variant Cse4 (CENP-A in human) to centromeric chromatin ensures faithful chromosome segregation. Mislocalization of overexpressed Cse4/CENP-A to non-centromeric regions contributes to chromosomal instability (CIN), an important hallmark of many cancers. Hence, defining mechanisms that prevent mislocalization of Cse4 is clinically significant. Here we report a role for YRA2 (Yeast RNA Annealing Protein 2) in ubiquitin mediated proteolysis of Cse4 to...

Recent advances in single-cell RNA sequencing and lineage tracing techniques have provided valuable insights into the temporal changes in gene expression during development, tumor progression, and disease onset. However, there are few computational methods available to analyze this information to help understand multicellular dynamics. We introduce Deep Lineage, a deep-learning method for analyzing time-series single-cell RNA sequencing with matched lineage tracing data. Our method accurately...

CONCLUSIONS AND RELEVANCE: This GBD 2023 analysis found that anorexia nervosa and bulimia nervosa contribute substantially to global nonfatal health loss. These findings support the integration of eating disorders into mental health surveillance, prevention, and service planning worldwide.

ClpP protease maintains proteostasis in human mitochondria and is overexpressed in cancers such as acute myeloid leukemia (AML). While activators such as dordaviprone (ONC201) have reached the clinic, the development of ClpP inhibitors has been hampered by paradoxical activation upon orthosteric inhibitor binding. Here, we report a series of quinazolinone-based compounds that allosterically inhibit human ClpP with nanomolar potency. Cryo-EM and H/D exchange mass spectrometry reveal that our lead...

Sialic acid (Neu5Ac) is a monosaccharide terminating glycoconjugates, serving as ligands for lectins in health and disease. Tools to target sialyltransferases (STs) and neuraminidases (NEUs) are important in the study of sialoglycans. 3FaxNeu5Ac is a common ST inhibitor, while 2,3diFNeu5Ac is a covalent mechanism-based NEU inactivator. Here, we demonstrate the advantages of having two fluorines at C3 for both classes of inhibitors. Motivated by the finding that 3FaxNeu5Ac is transferred by STs...

Effector-triggered immunity (ETI), mediated by nucleotide-binding leucine-rich repeat immune receptors (NLRs), plays a critical role in protecting plants from pathogens. While the scope of ETI elicited by Pseudomonas syringae type III effectors on Arabidopsis thaliana has been characterized, no equivalent study has been performed on related oilseed crops, limiting our ability to translate fundamental plant immunity research into crop protection strategies. Here, we present a comprehensive screen...

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CONCLUSION: BRIDGES-NBS has established a condition list for implementation across multiple state and territorial PHLPs, enabling the prospective evaluation of feasibility of population-wide genomic NBS.

In lytic infection, Epstein-Barr virus (EBV) proteins manipulate cellular processes in multiple ways to facilitate virion production and overcome host antiviral responses. Here, we screened a library of EBV lytic proteins for those that manipulate or localize to cellular processing bodies (PBs), known to play important roles in RNA surveillance and miRNA-mediated translational control. One EBV protein, BRRF1, was identified that partially localized to PBs, and affinity purification-mass...